The process of removing excess cells through programmed cell death is a fundamental mechanism by which developing epithelia are sculpted. A balance of death activators and inhibitors are required to determine whether a cell differentiates or dies; these activators are regulated by both cell intrinsic and extrinsic signals. Failure to properly activate cell death can lead to uncontrolled proliferation; this failure to regulate cells prone to oncogenic growth is a central feature of cancer. Conversely, aberrant degeneration of cells can lead to functional loss of important structures, particularly neurodegenerative diseases of the central and peripheral nervous system. In the retina, a variety of cell death-related diseases lead to photoreceptor and interneuron degeneration, the major causes of progressive blindness. Controlling these pathologies will require a better understanding of the mechanisms by which the proper balance of "life" and "death" signals within each cell are maintained. This proposal explores the control of programmed cell death during development of the Drosophila retina. A large-scale screen for genetic modifiers of the irreC-rst locus identified 170 mutations that are candidate cell death regulators. Of these, several are known cell death regulators and other extant genes are being examined to determine their role in death. Importantly, nine complementation groups were identified that specifically regulate the cell death process; based on their map positions, these mutations represent nine new cell death regulatory loci. The detailed phenotypes of these nine death-specific loci are being examined by a variety of means. These include new morphological tools such as live visualization of the cell death process, laser ablation to explore the role of specific cells, and organ culturing to permit the use of pharmacological agents. In addition, a variety of approaches are being used to fine map each of these nine loci in order to identify the corresponding molecular locus. Biochemical studies will further define the role of these factors in controlling the spatial aspects of epithelial sculpting and maturation.